Scientists at University of Texas MD Anderson Cancer Center are concerned with the issue of introducing “biosimilars” into the United States market. Biosimilars are analogous to generic versions of a patented therapeutic compound, but they are made by or derived from living organisms. “It’s not quite like synthesizing something in a test tube,” said Leonard Zwelling, MD, MBA, at MD Anderson.
Manufactured biosimilars are in demand because physicians, regulators, and patients want to reduce the costs of name-brand biologics. Biologics worldwide generated $46 billion in 2002 and brought in $169 billion in 2012, but many of the blockbuster drugs will be losing market protection within the next decade: adalimumab (Humira, Abbott) in 2016 and trastuzumab (Herceptin, Genetech) in 2019 are just two examples. This would open the door for companies looking to make money by selling cheaper versions of these drugs. “We definitely need biosimilars as a strategy to reduce our health care costs,” said Edward Li, PharmD, from the University of New England, in a recent web conference hosted by the Institute for Safe Medication Practices.
The trouble with generic biologics compared to generic small molecules is, according to Dr. Li, “When you consider small molecule drugs, those are relatively simple compared to a biologic manufacturing process.” For one, many biologics have molecular weights on the order of tens-of-thousands of Daltons. As an example, epoetin, a manufactured form of human erythropoietin used to stimulate red blood cell production, is 165 amino acids long and has a mass of 30,000 Da. It is a hundred times larger than the chemotherapeutic cisplatin, which weighs in at 300 Da.
Another hurdle is the actual manufacture of biologics. They require living cells, which add variability to the production process. Although a DNA transcript inserted into a cell may be identical to a DNA transcript inserted into another cell, the two resultant proteins will be slightly dissimilar due to post-translational modifications. These foldings and additions found in a biosimilar that are not found in the biologic may impact the biosimilar’s efficacy.
This could lead to problems with Food and Drug Administration (FDA) acceptance. The FDA requires that generic drugs show bioequivalence in form, safety, and route of administration during comparative clinical trials. There are currently three draft recommendations provided by the FDA to help manufacturers of biosimilars bring their drugs to market. Considering that the manufacture of biosimilars is approximately $250 million, according to John Mbagwu, PharmD, at the medical consulting group Optum, these recommendations are useful to prevent waste. However, this figure is small compared to the $1.2 billion average cost of bringing a new drug to market. “We are going to see some savings compared to the reference product,” said Dr. Li. “Hopefully that will increase access to expensive therapies.”
All would be well in a marketing perspective if biosimilars clear the FDA, but in order to make money, manufacturers need to ensure doctors will prescribe and patients are willing to buy biosimilars. The market research firm BioTrends found that only 30% of surveyed gastroenterologists would be willing to prescribe a biosimilar for inflammatory bowel disease that had been studied only in patients with rheumatoid arthritis. The drug, Remsima, a biosimilar of infliximab, was indicated for inflammatory bowel disease based on “indication extrapolation.” Further clinical data would need to be provided to label biosimilars as “interchangeable” for name-brand biologics. Even then, pharmacists would be required to notify prescribers which biosimilar was supplied. Said Dr. Zwelling, “Until I see a trial in which the biosimilar and the drug are compared head to head, in real patients with real cancer, I wouldn’t prescribe it, and I wouldn’t let my mother take it.”